1. Field of the Invention
The present invention relates to a dermal absorption-promoting agent comprising p-menthane-3,8-diol and 1,3-butylene glycol as well as a topical formulation containing the same.
The invention also relates to a dermal absorption-promoting agent comprising p-menthane-3,8-diol and 3-l-menthoxypropane-1,2-diol and a dermal absorption-promoting agent further comprising 1,3-butylene glycol, as well as a topical formulation containing such dermal absorption-promoting agents.
2. Prior Art
p-Menthane-3,8-diol is a substance contained in an eucalyptus plant, and is known to have a repelling effect on a mosquito. For example, each of Japanese Examined Patent Application Publication (JP-B) No. 3-80,138 and Japanese Patent Application Laid-Open (JP-A) No. 2-250,802 discloses a hazardous organism-repelling agent whose active ingredient is p-menthane-3,8-diol or a derivative thereof. In addition, each of Japanese Patent Application Laid open Nos. 5-294,828 and 6-40,875 discloses a dermal topical formulation which contains p-menthane-3,8-diol and whose repelling effect is sustained for a prolonged period, the latter disclosing a formulation having a further sustained repelling action when p-menthane-3,8-diol is combined with an antiinflammatory agent and/or an antihistamic agent.
When a drug is administered dermally, it has several advantageous characteristics by which the disadvantages associated with an oral administration or an injection is intended to be overcome. For example, a dermal administration allows a drug to be absorbed directly from a capillary vessel on a skin surface, thus avoiding a first pass effect in the liver and reducing side effects.
Such skin-penetrating property suitable for dermal administration is not possessed by all drugs, and it is required, when applying a dermal absorption system, to take a skin penetrating effect, skin compatibility and clinical demand into consideration. In addition, consideration of a combination with a substance having a dermal absorption-promoting effect for the purpose of promoting the skin penetration of a drug may also be required for exerting the efficacy of the drug.
Various substances having such dermal absorption-promoting effect are known and have been employed. For example, a safety test of a dermal absorption-promoting agent on the skin revealed that the dermal permeation of isosorbide dinitrate in an aqueous suspension was promoted greatly when combined with a monoterpene l-menthol, terpineol or 1,8-cineol (Fragrance Journal, p34, 1996-4). A journal xe2x80x9cYAKUZAIGAKUxe2x80x9d (vol.56, No.3 (1996) and DDS (Drug Delivery System, Vol. 12, No. 2 (1997)) also stated that l-menthol or 3-l-menthoxypropane-1,2-diol, when combined together with indomethacin, promotes the dermal absorption of indomethacin.
While l-menthol has already been known to promote the dermal absorption of a drug, it has a cool mint flavor, which may sometimes be too intense. On the other hand, 3-l-menthoxypropane-1,2-diol has a p-menthane structure similarly to l-menthol, and is a colorless, odorless, viscous liquid material formed by attaching a glycerin via an ether bond to the hydroxyl group of l-menthol, but its dermal permeation-promoting effect is somewhat lower than that of l-menthol. Nevertheless, since l-menthol and 3-l-menthoxypropane-1,2-diol have less formulation base selectivities and can be combined not only with hydrophilic formulation bases but also with lipophilic formulation bases, they are capable of being applied widely in the field of topical formulations, thus providing high utilities.
While both of l-menthol and 3-l-menthoxypropane-1,2-diol have p-menthane structures as described above, l-menthol, when employed in preparing a topical formulation, poses a complicated operation during a manufacturing process in order to suppress the too intensive mint flavor. In addition, a residual characteristic mint flavor in a pharmaceutical product makes the product less favorable for users.
On the other hand, 3-l-menthoxypropane-1,2-diol does not have a satisfactory dermal permeation-promoting ability, although it poses no flavor problems.
We made an effort in a study based on the fact that p-menthane-3,8-diol, which is extracted and collected from an eucalyptus plant and has a repelling effect on a mosquito, has a p-menthane structure similarly to l-menthol and 3-l-menthoxypropane-1,2-diol and finally discovered that p-menthane-3,8-diol has a dermal absorption-promoting effect, thus establishing the present invention.
Thus, the present invention provides a dermal absorption-promoting agent comprising p-menthane-3,8-diol and 1,3-butylene glycol as well as a topical formulation containing the same.
The invention also provides a dermal absorption-promoting agent comprising p-menthane-3,8-diol and 3-l-menthoxypropane-1,2-diol and a dermal absorption-promoting agent further comprising 1,3-butylene glycol, as well as a topical formulation containing such dermal absorption-promoting agents.